Abstract
Mitochondrial dysfunction plays a pivotal role in the progression of Alzheimer's disease (AD), and yet the mechanisms underlying the impairment of mitochondrial function in AD remain elusive. Recent evidence suggested a role for Presenilins (PS1 or PS2) in mitochondrial function. Mutations of PSs, the catalytic subunits of the γ-secretase complex, are responsible for the majority of inherited AD cases (FAD). PSs were shown to be present in mitochondria and particularly enriched in mitochondria-associated membranes (MAM), where PS2 is involved in the calcium shuttling between mitochondria and the endoplasmic reticulum (ER). We investigated the precise contribution of PS1 and PS2 to the bioenergetics of the cell and to mitochondrial morphology in cell lines derived from wild type (PS+/+), PS1/2 double knock-out (PSdKO), PS2KO and PS1KO embryos. Our results showed a significant impairment in the respiratory capacity of PSdKO and PS2KO cells with reduction of basal oxygen consumption, oxygen utilization dedicated to ATP production and spare respiratory capacity. In line with these functional defects, we found a decrease in the expression of subunits responsible for mitochondrial oxidative phosphorylation (OXPHOS) associated with an altered morphology of the mitochondrial cristae. This OXPHOS disruption was accompanied by a reduction of the NAD+/NADH ratio. Still, neither ADP/ATP ratio nor mitochondrial membrane potential (ΔΨ) were affected, suggesting the existence of a compensatory mechanism for energetic balance. We observed indeed an increase in glycolytic flux in PSdKO and PS2KO cells. All these effects were truly dependent on PS2 since its stable re-expression in a PS2KO background led to a complete restoration of the parameters impaired in the absence of PS2. Our data clearly demonstrate here the crucial role of PS2 in mitochondrial function and cellular bioenergetics, pointing toward its peculiar role in the formation and integrity of the electron transport chain.
Highlights
Metabolic dysfunction is central in Alzheimer’s disease (AD) since it appears at very early stage of the disorder, even before clinical symptoms (Chen and Zhong, 2013)
The overall profile of Oxygen consumption rate (OCR) and the parameters related to the oxidative phosphorylation (OXPHOS) activity measured before or after drug addition, that are basal respiration, coupling and spare respiratory capacity were all impaired in PS1/2 double knock-out (PSdKO) and PS2KO cells (Figures 1C–F)
In both approaches (FC and direct fluorescence measurements), no significant differences in were observed between the different populations of mouse embryonic fibroblast (MEF), oxygen consumption was altered in PS2KO and PSdKO cells
Summary
Metabolic dysfunction is central in Alzheimer’s disease (AD) since it appears at very early stage of the disorder, even before clinical symptoms (Chen and Zhong, 2013). Mitochondria are known as the powerhouse of the cell for their capacity to supply energy, but they are critical in other cellular processes such as apoptosis, reactive oxygen species (ROS) production (Paradies et al, 2014), and calcium homeostasis (Osellame et al, 2012) All these processes turn out to be affected in AD pathology (Hroudova et al, 2014). In cytoplasmic hybrid (cybrid) cell lines, generated by insertion of platelets’ mitochondria collected from sporadic AD (SAD) patients into human neuroblastoma cells (SHSY5Y) depleted of mitochondria, bioenergetics dysfunctions such as oxidative phosphorylation (OXPHOS) and glucose utilization defects have been observed (Silva et al, 2013) These metabolic perturbations found in AD raised a chicken and the egg issue, namely to define whether mitochondrial dysfunction is a cause or a consequence in this pathology
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